Coronary artery vasospasm (CAVS), a transient constriction of coronary arteries, leads to diminished or complete blockage of blood flow. This condition, distinct from classic angina, was first characterized by Dr. Myron Prinzmetal in 1959, expanding upon Heberden’s 1772 description of angina. CAVS can manifest across the spectrum of angina, from stable presentations to acute coronary syndromes, triggered by acute ischemia. Characteristically heterogeneous, CAVS diverges from typical coronary artery disease risk factors. This article provides an in-depth exploration of Coronary Vasospasm Diagnosis and management, emphasizing the crucial roles of a multidisciplinary healthcare team in optimizing patient outcomes.
Delving into the Causes of Coronary Artery Vasospasm
The etiology of coronary artery vasospasm (CAVS) is complex and multifactorial, stemming from an interplay of autonomic nervous system activity, inflammatory processes, oxidative stress, endothelial dysfunction, smooth muscle cell hypercontractility, genetic predispositions, and lifestyle factors. Prinzmetal’s foundational 1959 canine study highlighted the effects of arterial occlusion and release, observing pain, anginal symptoms, ischemic ECG changes, and systolic ballooning, thus postulating vasospasm in epicardial coronary arteries as a cause.
Epidemiology of Coronary Artery Vasospasm
Coronary artery vasospasm (CAVS) is most prevalent in individuals aged 40 to 70, with incidence decreasing after 70. Geographical distribution varies, with a higher incidence reported in Japanese populations compared to Western populations. Furthermore, provocative testing reveals multiple spasms more frequently in Japanese individuals (23%) than in Caucasians (7.5%). A German study indicated that CAVS was responsible for symptoms in approximately half of patients without obstructive coronary artery disease who were tested with acetylcholine.
Pathophysiology of Coronary Artery Vasospasm: Unraveling the Mechanisms
The exact pathogenesis of coronary artery vasospasm (CAVS) is still being elucidated, involving a complex interplay of factors. Initially, autonomic nervous system dysregulation was considered primary, but subsequent research has highlighted the roles of endothelial dysfunction, oxidative stress, magnesium deficiency, respiratory alkalosis, and even genetic factors. Central to CAVS development is the hyperreactivity and hypertonicity of coronary vessel smooth muscle.
Autonomic Nervous System Imbalance
Both parasympathetic and sympathetic nervous system activity increases have been implicated in CAVS. Typically, CAVS episodes occur nocturnally, coinciding with parasympathetic nervous system activation. Acetylcholine, a parasympathetic neurotransmitter, is known to induce CAVS, supporting this link. However, nocturnal CAVS often occurs during REM sleep, characterized by reduced vagal tone and adrenergic surges. Elevated catecholamine levels, associated with sympathetic activity, can also trigger CAVS, indicating a complex, still-unfolding relationship between the autonomic nervous system and CAVS.
Endothelial Dysfunction: A Key Player
Dysfunctional endothelial nitric oxide (NO) synthase and reduced NO release are strongly linked to CAVS. In healthy endothelium, acetylcholine, serotonin, and histamine induce vasodilation by releasing NO. However, in endothelial dysfunction, these agents can paradoxically provoke CAVS. It’s important to note that endothelial dysfunction isn’t universally present in CAVS patients, suggesting other contributing factors.
Oxidative Stress and Vascular Health
Oxidative stress, characterized by increased reactive oxygen species (ROS), significantly impairs vascular health. ROS contribute to inflammation, endothelial damage, and vasoconstriction, leading to vascular dysfunction and remodeling. Smoking, for instance, reduces acetylcholine-dependent relaxation, indicating ROS-mediated NO destruction. However, the precise role of oxidative stress in CAVS is intricate, as not all CAVS patients exhibit endothelial NO deficiency or dysfunction.
Smooth Muscle Cell Hypercontractility: The Cellular Level
Research by Shimokawa et al. identified enhanced myosin light-chain phosphorylation as a critical factor in CAVS. Their work suggests the involvement of a hydroxyfasudil-sensitive Rho-kinase-mediated pathway in this phosphorylation. Rho-kinase inhibitors, therefore, hold potential for inhibiting vasospastic activity. Further investigations, including studies on K mutant and SUR2 K knockout mice, have revealed that loss of function in K channels can induce smooth muscle cell hypercontraction independent of atherosclerosis. These findings are crucial for understanding smooth muscle hypercontractility’s role in human CAVS.
Genetic Predisposition: Uncovering the Links
While no direct genetic link definitively explains all CAVS cases, genetic polymorphism is increasingly recognized as a contributing factor. Mutations or polymorphisms in genes like endothelial NO synthase and paraoxonase I have been observed in CAVS patients. Other genetic variations in adrenergic and serotoninergic receptors, angiotensin-converting enzyme, and inflammatory cytokines are also implicated, suggesting a complex genetic landscape underlying CAVS susceptibility.
Histopathology of Coronary Artery Vasospasm
Inflammation is a recognized component of coronary artery vasospasm (CAVS) histopathology. Inflammatory cell infiltration, particularly mast cells, is observed in CAVS. Mast cells have been found at CAVS sites, within the adventitia, and in coronary artery plaques of affected individuals, indicating their potential role in the vasospastic process.
History and Physical Examination in Coronary Vasospasm Diagnosis
A significant portion (20% to 30%) of patients evaluated for obstructive coronary artery disease due to chest pain have normal coronary angiograms. Among these, some may experience coronary artery vasospasm (CAVS). Symptoms may include typical angina, notably at rest, especially during the night and early morning, and reduced morning exercise tolerance. Patients often describe crushing, substernal chest pain, potentially radiating to the jaw or arm, relieved by sublingual nitroglycerin. Physical examination should include a comprehensive cardiovascular assessment, focusing on vital signs, hemodynamic stability, heart sounds (rhythm, rate, murmurs, S3 or S4), and a pulmonary exam to detect crackles indicative of pulmonary edema.
Evaluation and Coronary Vasospasm Diagnosis
Electrocardiogram (ECG) is crucial during a suspected CAVS episode. Hallmark ECG changes include ST-segment elevation corresponding to the occluded vessel and ST depression in contralateral leads. Prompt resolution of ECG changes with fast-acting nitrates strongly supports the diagnosis. In some instances, only ST depression in contiguous leads may be observed. Other ECG findings during recovery or active spasm include negative T waves and U waves in the affected territory.
Cardiac biomarkers, such as troponin I or C and creatinine kinase, may be assessed, but their elevation is not consistently present in CAVS-induced chest pain.
Coronary angiography with provocative testing remains the gold standard for definitive coronary vasospasm diagnosis. Provocative testing involves inducing vasospasm under controlled conditions during angiography. A positive test, confirming coronary vasospasm diagnosis, is defined by significant luminal narrowing (50%, 70%, 75%, or 90%) accompanied by symptoms and ECG changes, which is subsequently reversed by intracoronary nitroglycerin administration. In the United States, methylergonovine (ergonovine) and acetylcholine are commonly used provocative agents, inducing vasoconstriction in arteries with endothelial dysfunction.
Image alt text: ECG showing ST-segment elevation, a key diagnostic indicator for coronary vasospasm during an episode.
Treatment and Management Strategies for Coronary Artery Vasospasm
Medical therapy and risk factor modification are fundamental to CAVS management. Initial treatment focuses on nitrates and calcium channel blockers. Nitrates relax vascular smooth muscle by activating guanylate cyclase and increasing cGMP production. Calcium channel blockers reduce calcium influx into vascular smooth muscle, effectively preventing spasm.
Alternative therapies under investigation include nicorandil (a nitrate and K-channel activator), statins, fasudil (a rho kinase inhibitor), aspirin, magnesium, vitamins C and E, iloprost, alpha-receptor blockers, selective serotonin reuptake inhibitors, and selective thromboxane A2 synthetase inhibitors. While some show promise, further research is needed before these can be considered mainstream treatments like nitrates and calcium channel blockers. Beta-blockers are generally avoided as they can exacerbate vasospastic angina.
While vasodilators typically relieve CAVS, a subset of patients (around 20%) exhibits drug-resistant vasospastic disease. Percutaneous balloon angioplasty has not shown consistent benefit in these cases. Percutaneous coronary intervention (PCI) with stenting, combined with ongoing medical therapy, is considered for patients with significant stenosis due to CAVS, but recurrent vasospasm in different locations remains a challenge.
The role of implantable cardioverter-defibrillators (ICDs) in CAVS patients presenting with ventricular tachycardia or fibrillation is still under investigation. However, positive outcomes have been reported in patients surviving life-threatening ventricular arrhythmias attributed to CAVS who received ICDs.
Differential Diagnosis of Coronary Artery Vasospasm
The variable presentation of coronary artery vasospasm (CAVS) necessitates differentiation from several cardiac conditions. Conditions to consider include obstructive atherosclerotic coronary artery disease, pericarditis or myopericarditis, primary arrhythmias, and stress-induced cardiomyopathy. The diagnostic challenge lies in CAVS’s inconsistent presentation with chest pain, ECG changes, and biomarker elevation.
Prognosis of Coronary Artery Vasospasm
Recurrent angina episodes occur in 4% to 19% of CAVS patients. Advanced age and impaired left ventricular function are associated with poorer prognosis in CAVS-related acute coronary syndromes. Elevated high-sensitivity C-reactive protein (hs-CRP) levels also indicate increased risk of death, non-fatal myocardial infarction, and recurrent angina requiring repeat angiography. However, with consistent calcium channel blocker therapy and management of risk factors like smoking, the overall prognosis is generally favorable.
Complications of Coronary Artery Vasospasm
Potential complications of coronary artery vasospasm (CAVS) include:
- Life-threatening arrhythmias
- Myocardial infarction
- Sudden cardiac death
Deterrence and Patient Education for Coronary Artery Vasospasm
Patient counseling regarding modifiable risk factors, particularly smoking cessation, is crucial in CAVS management. Treatment strategies emphasize initiating and maintaining maximally tolerated doses of calcium channel blockers. Patient education should stress medication adherence and the risks associated with non-compliance, including recurrent CAVS episodes.
Clinical Pearls and Key Considerations in Coronary Vasospasm Diagnosis
Given the diverse symptom presentation, coronary artery vasospasm (CAVS) should be considered in the differential diagnosis of patients presenting with chest pain. Distinguishing CAVS from obstructive atherosclerotic coronary artery disease is critical due to differing treatment approaches. The recurrence of symptoms in CAVS underscores the need for ongoing research into its pathogenesis and optimal treatment strategies.
Enhancing Healthcare Team Outcomes in Coronary Vasospasm Management
Effective management of coronary artery vasospasm (CAVS) necessitates a collaborative interprofessional team approach. Primary care providers and nurse practitioners play a vital role in patient education about atherosclerosis and modifiable risk factors for coronary disease. Patient education should emphasize lifestyle modifications, such as smoking cessation, and the importance of medication adherence to prevent recurrent CAVS attacks. Due to the potential for recurrent and sometimes fatal vasospasm, close monitoring and ongoing research are essential to improve understanding and treatment of CAVS (Level V evidence).
References
1.Beijk MA, Vlastra WV, Delewi R, van de Hoef TP, Boekholdt SM, Sjauw KD, Piek JJ. Myocardial infarction with non-obstructive coronary arteries: a focus on vasospastic angina. Neth Heart J. 2019 May;27(5):237-245. [PMC free article: PMC6470236] [PubMed: 30689112]
2.Cho SG, Kim Y, Jeong MH, Bom HS. Myocardial Infarction With Nonobstructive Coronary Arteries Assessed by 11C-Acetate Cardiac PET. Clin Nucl Med. 2019 Mar;44(3):e166-e167. [PubMed: 30672752]
3.Han SH, Lee KY, Her SH, Ahn Y, Park KH, Kim DS, Yang TH, Choi DJ, Suh JW, Kwon HM, Lee BK, Gwon HC, Rha SW, Jo SH, Ko KP, Baek SH. Impact of multi-vessel vasospastic angina on cardiovascular outcome. Atherosclerosis. 2019 Feb;281:107-113. [PubMed: 30658185]
4.Bertic M, Chue CD, Virani S, Davis MK, Ignaszewski A, Sedlak T. Coronary Vasospasm Following Heart Transplantation: Rapid Progression to Aggressive Cardiac Allograft Vasculopathy. Can J Cardiol. 2018 Dec;34(12):1687.e9-1687.e11. [PubMed: 30527163]
5.Teragawa H, Oshita C, Ueda T. Coronary spasm: It’s common, but it’s still unsolved. World J Cardiol. 2018 Nov 26;10(11):201-209. [PMC free article: PMC6259026] [PubMed: 30510637]
6.Lim Y, Singh D, Loh PH, Poh KK. Multivessel coronary artery spasm in pericarditis. Singapore Med J. 2018 Nov;59(11):611-613. [PMC free article: PMC6250754] [PubMed: 30498841]
7.Park SH, Choi BG, Rha SW, Kang TS. The multi-vessel and diffuse coronary spasm is a risk factor for persistent angina in patients received anti-angina medication. Medicine (Baltimore). 2018 Nov;97(47):e13288. [PMC free article: PMC6392675] [PubMed: 30461639]
8.Takeyoshi D, Kikuchi S, Miyake K, Tatsukawa T, Kobayashi D, Uchida D, Kitani Y, Kamiya H, Azuma N. Fatal Vasospasm of the Coronary Arteries in a Patient Undergoing Distal Bypass Surgery and Endovascular Therapy for Threatened Lower Limbs Due to Acute Exacerbation of Peripheral Arterial Disease. Ann Vasc Dis. 2018 Sep 25;11(3):369-372. [PMC free article: PMC6200607] [PubMed: 30402193]
9.Slavich M, Patel RS. Coronary artery spasm: Current knowledge and residual uncertainties. Int J Cardiol Heart Vasc. 2016 Mar;10:47-53. [PMC free article: PMC5462634] [PubMed: 28616515]
10.Hung MJ, Hu P, Hung MY. Coronary artery spasm: review and update. Int J Med Sci. 2014;11(11):1161-71. [PMC free article: PMC4166862] [PubMed: 25249785]
11.Picard F, Sayah N, Spagnoli V, Adjedj J, Varenne O. Vasospastic angina: A literature review of current evidence. Arch Cardiovasc Dis. 2019 Jan;112(1):44-55. [PubMed: 30197243]
12.Benamer H, Millien V. [Coronary spasm a diagnostic and therapeutic challenge]. Presse Med. 2018 Sep;47(9):798-803. [PubMed: 30245142]
